α-Conotoxin Peptidomimetics: Probing the Minimal Binding Motif for Effective Analgesia

Several analgesic alpha-conotoxins have been isolated from marine cone snails. Structural modification of native peptides has provided potent and selective analogues for two of its known biological targets-nicotinic acetylcholine and gamma-aminobutyric acid (GABA) G protein-coupled (GABA(B)) receptors. Both of these molecular targets are implicated in pain pathways. Despite their small size, an incomplete understanding of the structure-activity relationship of alpha-conotoxins at each of these targets has hampered the development of therapeutic leads. This review scrutinises theN-terminal domain of the alpha-conotoxin family of peptides, a region defined by an invariant disulfide bridge, a turn-inducing proline residue and multiple polar sidechain residues, and focusses on structural features that provide analgesia through inhibition of high-voltage-activated Ca(2+)channels. Elucidating the bioactive conformation of this region of these peptides may hold the key to discovering potent drugs for the unmet management of debilitating chronic pain associated with a wide range of medical conditions.